Autism (autistic disorder) is a pervasive developmental disorder with diagnostic criteria based on abnormal social interactions, language abnormalities, and stereotypes evident prior to 36 months of age [5]. Despite its lack of Mendelian transmission autism is highly genetically determined [6].
The vast majority of cases of autism are unrelated to known teratogens but the phenotypic expression of autism may be affected by the interaction of environmental factors with multiple gene loci. There is evidence supporting a role for oxidative stress in autism [7, 8]. Oxidative stress could interact with common functional polymorphic variants of genes that protect against oxidative stress and could thus affect brain development during gestation or possibly after gestation, contributing to expression of autism. Glutathione (GSH) is the most important endogenous antioxidant due to its ability to bind electrophilic substrates through its free sulfhydryl group [9] and is the most abundant non-protein thiol, occurring in millimolar concentrations in human tissues [10]. Low plasma total GSH (tGSH) levels, elevated levels of oxidized GSH (GSSG) and low ratios of tGSH:GSSG have been reported in autism [11].
Glutathione-S-transferases (GSTs), are an important class of antioxidant enzymes that catalyze conjugation of GSH to toxic electrophiles. GSTs are abundant, accounting for up to 10% of cellular protein [12]. Some genetic polymorphisms of GSTs are known to affect enzyme function. It is possible that a functional GST polymorphism could contribute to the pathogenesis of autism, an effect that could be potentiated by reduced levels of GSH, one of the substrates of GSTs. GSTs are Phase II enzymes that conjugate GSH to activated toxins, xenobiotics and metabolites including products of Phase I enzymes such as cytochrome P450 oxidases.
Despite technological advances, not all loci in the human genome can readily be fully genotyped using current conventional methods. Incomplete sequence information, unknown splice junction, unknown size of the deletion, and a large amount of homology with nearby sequence can all contribute to such a problem. In addition, there remains a need for methods and assays to determine susceptibility to and provide diagnosis of autism. Improved methods and additional relevant autism genetic markers are therefore needed.
The citation of references herein shall not be construed as an admission that such is prior art to the present invention.